Tissue adhesives have many potential medical applications, including wound closure, supplementing or replacing sutures or staples in internal surgical procedures, adhesion of synthetic onlays or inlays to the cornea, drug delivery devices, and as anti-adhesion barriers to prevent post-surgical adhesions. Conventional tissue adhesives are generally not suitable for a wide range of adhesive applications. For example, cyanoacrylate-based adhesives have been used for topical wound closure, but the release of toxic degradation products limits their use for internal applications. Fibrin-based adhesives are slow curing, have poor mechanical strength, and pose a risk of viral infection. Additionally, the Fibrin-based adhesives do not covalently bind to the underlying tissue.
Several types of hydrogel tissue adhesives have been developed, which have improved adhesive and cohesive properties and are nontoxic. These hydrogels are generally formed by reacting a component having nucleophilic groups with a component having electrophilic groups, which are capable of reacting with the nucleophilic groups of the first component, to form a crosslinked network via covalent bonding. However, these hydrogels typically swell or dissolve away too quickly, or lack sufficient adhesion or mechanical strength, thereby decreasing their effectiveness as surgical adhesives.
Kodokian et al. (copending and commonly owned U.S. Patent Application Publication No. 2006/0078536) describe hydrogel tissue adhesives formed by reacting an oxidized polysaccharide with a water-dispersible, multi-arm polyether amine. These adhesives provide improved adhesion and cohesion properties, crosslink readily at body temperature, maintain dimensional stability initially, do not degrade rapidly, and are nontoxic to cells and non-inflammatory to tissue. However, a tissue adhesive having these properties in addition to also having a cationic charge to promote wound healing and blood coagulation, while providing antimicrobial properties would be highly desirable.
Oxidized crosslinked polysaccharides having a chemically induced charge have been reported to be useful for treating wounds (Gruskin et al., U.S. Pat. No. 5,502,042) and for reducing scar formation (Gruskin et al. U.S. Pat. Nos. 6,410,519 and 6,756,518). Additionally, a polysaccharide-based hydrogel formed by reacting oxidized dextran and chitosan for use as a tissue adhesive is described by Goldmann (U.S. Patent Application Publication No. 2005/0002893) and Odermatt et al. (U.S. Patent Application Publication No. 2006/0292030).
Therefore, the problem to be solved is to provide a tissue adhesive material with improved adhesion and cohesion properties, that crosslinks readily at body temperature, maintains dimensional stability initially, does not degrade rapidly, is nontoxic to cells and non-inflammatory to tissue, and has a cationic charge for use in surgical procedures as well as other medical applications. The stated problem is addressed herein by the discovery that hydrogels formed by reaction of an oxidized cationic polysaccharide containing aldehyde groups and amine groups with a multi-arm amine possess these desired properties.